Metal stent with surface layer of noble metal oxide and method of fabrication

ABSTRACT

In a process for producing a biocompatible stent, a tubular substrate of the stent adapted for diametric expansion has a layer of a noble metal oxide formed over at least the outer surface of greater diameter of the substrate, the substrate being composed of a metal or an alloy thereof that is non-noble or less-noble than the layer&#39;s noble metal. An interface region adapted to prevent corrosion and to provide a firm bond between the surface of the substrate and the noble metal oxide layer is established, at least in part, by forming the noble metal oxide layer with a progressively varying concentration of noble metal-to-oxide with depth of the layer such that a surface of pure noble metal and negligible oxide of the layer is in closest proximity to the surface of the substrate. In one embodiment of the process, the interface region is established by forming the surface of pure noble metal and negligible oxide thereof in direct contact with the metal or alloy of the substrate surface. In another, the interface region is established by first creating an oxide of the substrate metal or alloy thereof at the substrate surface, and then forming the noble metal oxide layer as above, but in contact with the substrate metal or alloy oxide. Alternatively, the noble metal oxide layer has no progressively varying concentration but simply overlies an oxide of the substrate metal or alloy.

BACKGROUND OF THE INVENTION

[0001] The present invention relates generally to body implantablestents, deployed in a vessel, tract, channel or duct, such as a coronaryartery or femoral artery of a patient to maintain its lumen open forsatisfactory blood flow therethrough, and more particularly to methodsof producing multi-layer stent structures in which an oxide of a noblemetal or alloy is bonded in a firm and stable relationship to anunderlying non-noble or less-noble metal, and to such stent structuresthemselves.

[0002] When inserted and deployed in a vessel, duct, channel or tract(referred to generally herein, for convenience, as a vessel) of thebody—for example, a coronary artery after dilatation of the artery byballoon angioplasty—a stent acts as a scaffold to maintain the vessel'slumen open. The stent prosthesis is structured as an open-ended tubularelement with through-holes in its sidewall to allow expansion of itsdiameter from a first sufficiently small size to permit navigation ofthe stent, mounted on a balloon catheter, through the vessel to thetarget site where it is to be deployed, to a second fully deployedsufficiently large size to engage the inner lining of the vessel's wallfor retention at the target site.

[0003] A coronary artery, for example, may become occluded from abuildup of fatty deposits or plaque on the inner lining of the vessel'swall. The artery blockage may be detected through an electrocardiogramperformed during the individual's visit to a doctor, or be so extreme asto result in angina or even myocardial infarction. Typically, theprocedure performed to relieve the blockage is balloon angioplasty, inwhich a balloon catheter is inserted into the vessel until the balloonis at the target site as monitored under fluoroscopy, the balloon isinflated to compress the fatty deposits against the inner lining of thevessel wall to open the lumen, and the catheter is then withdrawn fromthe patient. Other procedures may alternatively be performed forrelieving the blockage, but for a relatively large percentage ofangioplasty patients a new blockage of the treated vessel typicallyoccurs only a few months later. The new blockage is usually attributableto trauma to the vessel wall that arises from the original angioplastyprocedure, but the mechanism responsible for this restenosis orre-occlusion of the vessel lumen is intimal hyperplasia, a rapidproliferation of smooth muscle cells along the treated region of thevessel wall, quite different from the causation of the originalblockage.

[0004] As noted above, it is customary to install a stent at the traumasite to maintain the vessel lumen open, often in a procedureaccompanying or shortly after the angioplasty procedure. The stent ismounted in a crimped state on the balloon of a balloon catheter foradvancement through the appropriate portion of the patient'scardiovascular system to the target site, also under x-ray fluoroscopy,where the balloon is inflated to deploy the stent by expansion of thestent diameter under the outwardly directed radial pressure exerted bythe balloon. The outer surface of the stent is thereby forced intoengagement with and exerts pressure on the inner lining of the vesselwall. The stent structure has sufficient resilience to allow somecontraction of the diameter of the stent under the force exerted on itby the natural recoil of the vessel wall, but has sufficient stiffnessto largely withstand the recoil and hold open the lumen of the vessel atthe implant site.

[0005] The presence of the stent in contact with the vessel wall,however, can promote hyperplasia and resulting restenosis, and, alongthe stent's inner surface, may promote thrombus formation with theperfusion of blood through the stent's lumen. To avoid acute blockage ofthe vessel lumen owing to these reactions in some patients, drug coatedstents are being prescribed on an almost regular basis. The outersurface of the stent to be implanted may be coated with anantiproliferative or immunosuppressive agent, while the inner surfacemay be coated with an antithrombotic agent. Drug coated stents areconsiderably more expensive than uncoated stents, and may be unnecessaryfor a relatively large percentage of angioplasty patients in which theyare implanted, being prescribed solely to avoid the possibility of anundesirable reaction soon thereafter.

[0006] On the other hand, the use of uncoated stents has its own set ofproblems even beyond possibly inducing a traumatic response along thevessel wall or promoting thrombosis along the stent's lumen. Thematerial of which the stent is composed can induce an allergic reactionin a statistically significant percentage of the patient population.These include commonly used stent materials such as chrome, nickel, andeven medical grade 316L stainless steel—which contains about 16% nickel.Stent implants are contraindicated in many such allergic patients.Wholly biodegradable stents of possibly sufficient radial strength areundergoing testing but appear unlikely to constitute a breakthrough or asatisfactory solution in these cases.

[0007] Another consideration in material selection is the need for theimplanting physician to be able to see the advancement and positioningof the stent as it is being implanted at the specified target site inthe body, typically by x-ray fluoroscopy. The thickness of a metallicstent wall is made sufficient to withstand the aforementioned vesselwall recoil that invariably follows stent deployment and to hold thevessel lumen open. But it is also necessary that the calculation ofstent wall thickness take into account the dimension necessary to renderthe stent visible with fluoroscopy, given the type of material of whichthe stent is composed. Various materials, such as 316L stainless steel,possess suitable mechanical strength to maintain an open vessel lumen,with smaller wall thickness than is required to provide fluoroscopicvisibility. Typical conventional stent wall or wire thicknesses haveranged up to about 200 microns (or micrometers, μm). A 70 to 80 μm thick316L steel stent, for example, offers sufficient mechanical strength forthe aforementioned purposes, but is too thin to create the shadow neededfor fluoroscopic viewing because the x-ray absorption of this metal isso low. Increasing the wall thickness of the stent to enhance itsradiopacity makes the stent less flexible, which adversely affects itsmaneuverability through narrow vessels during implantation, and its easeof expansion during deployment, with concomitant increased risk ofballoon rupture.

[0008] It follows that for successful interventional use, the stentshould possess characteristics of relatively non-allergenic reaction,good radiopacity, freedom from distortion on magnetic resonance imaging(MRI), flexibility with suitable elasticity to be plasticallydeformable, resistance to vessel recoil, sufficient thinness to minimizeobstruction to flow of blood (or other fluid or material in vessels thatrequire stenting other than the cardiovascular system), andbiocompatibility to avoid vessel re-occlusion. Stent material, as wellas stent design, plays a role in achieving these characteristics.

[0009] Aside from vascular usage, other vessels of the human body inwhich a stent might be installed to maintain an open lumen include thetracheo-bronchial system, the biliary hepatic system, the esophagealbowel system, and the urinary tract, to name a few. Many of the samerequirements are found in these other endoluminal usages of stents.

[0010] Despite improvements in the design, construction and coating ofcoronary stents, restenosis remains a problem. A major contributingfactor is the inability of the body to quickly incorporate the implantedforeign material of the stent. Basic research with cell cultures, aswell as animal experiments, demonstrate that the degree ofendothelialization of the foreign body is a determinant of the amount ofthe restenosis caused by the presence of that body. It had been assumedby industry practitioners and researchers that a highly polished andsmooth surface is beneficial to prevent stent thrombosis and tofacilitate endothelialization, but more recent experiments indicate thismay not be entirely true.

[0011] A main reason for the lack of sufficient clinical success ratewith electropolished stents is that the smooth muscle cells that seek toenvelop a foreign body must undergo greater proliferation to cover thepolished stent. The continuing flow of blood with high pressure and highshearing stress prevents the migration of smooth muscle cells thatproliferate from the media and adventitial cells of a stented vesselsuch as a coronary artery. Indeed, a slightly rough surface appears tofacilitate considerably more coverage by smooth muscle cells, whichleads to a functional endothelial layer some 10 to 14 days after stentimplantation. A single layer of endothelial cells has been found to sealthe neointima, and thereby to prevent the stimulus that facilitatesproliferation of cells beyond mere coverage of the foreign body.

[0012] As is intuitively obvious, the thinner the stent strut, the lesswall thickness of the stent invades the lumen of the stented vessel. Anda thin stent is more easily covered by a neoendothelial build-up.Accordingly, it is desirable to make the stent wall as thin as possible.But, again, fluoroscopic visibility of the structure has a role indetermining its thickness for a given material.

[0013] Some improvement in visibility is achieved by application of anadherent, more radiopaque layer to the surface of a stent core materialof medical grade implantable 316L stainless steel. These radiopaquelayer materials include gold and certain other noble metals, such asplatinum. Their considerably greater radiopacity relative to stainlesssteel renders the stent highly visible under fluoroscopy. The materialsare also substantially non-allergenic and non-thrombogenic. The coatingmay be applied in a very thin layer, leaving the determinant of stentwall thickness almost solely the requirement of mechanical strength. Thecoating must be capable of absolute adherence to the underlying metal ofthe stent to avoid cracking or defects in the homogeneous overlyinglayer, and sufficient resistance to peeling or flaking of the coatingmaterial both during insertion of the stent, expansion of the diameterof the stent as it is being deployed in final position, and throughoutthe entire time the stent remains in that position—objectives which arenot easily achievable. The presence of cracks or related defects in thesurface coating can produce a galvanic potential that could ultimatelylead to corrosion of the underlying steel or lesser metal, anunacceptable situation for a device intended to be permanently implantedin the body. Therefore, manufacturing requires a high degree of qualitycontrol and concomitant high cost.

[0014] U.S. Pat. No. 6,099,561, of the same assignee, discloses a stentstructure with three fundamental layers, a first underlying substrate ofa stent metal that functions to provide high mechanical strength, asecond intermediate layer that functions to provide high fluoroscopicvisibility—such as a noble metal layer or alloy thereof—, and a toplayer of a particularly beneficial biocompatible material—designated tobe a ceramic-like material such as iridium oxide or titanium nitride.The intermediate layer of elemental noble metal or an alloy thereof isuninterrupted by gaps or pockets along its length, and is highlyadherent for tight coverage and substantially uniform thickness. Thisintermediate layer tends to avoid the creation of a galvanic potentialthat would lead to corrosion of the lesser, underlying metal. Such acondition might otherwise exist if, without the presence of anintermediate uninterrupted noble metal layer, a layer of ceramic-likemetal were to overlie and adhere to the base metal at points wherefissures could exist. The multi-layer stent of the '561 patent exhibitsmechanical strength, small physical dimensions, increased visibility,long-term stability, and a highly biocompatible surface that enablesrapid endothelialization with low occurrence of restenosis. But it isexpensive to produce.

[0015] U.S. Pat. No. 6,387,121, of the same assignee as the presentapplication, discloses a multi-layer stent with a thin, continuousintermediate layer of metal or alloy of niobium, zirconium, titanium ortantalum overlying the surface of the stent's tubular metal base, and anouter layer of iridium oxide overlying the intermediate layer withinterstices for storing and dispensing (eluting) drugs.

[0016] U.S. Pat. No. 6,478,815, also assigned to the same assignee asthis application, discloses a stent composed of niobium with a trace ofanother metal, such as zirconium, titanium or tantalum for alloyformation and reinforcement. Also, a surface coating of iridium oxide ortitanium nitrate may be applied to the niobium structure to aid ininhibiting vessel closure, as with the previous patent disclosuresmentioned herein. This stent is beneficial, enjoying many of theadvantages that have been sought as discussed above, with only twolayers in the stent structure.

[0017] A stability problem may be encountered in the bond between thenoble metal oxide layer, such as iridium oxide, and a non-noble orless-noble metal, alloy or compound, such as niobium or platinumenriched medical grade stainless steel. During the bonding process theless noble metal tends to draw or leach oxygen atoms from the noblemetal, which causes depletion of oxygen from the latter metal. Theresult can be a less stable, less satisfactory bond or adhesion betweenthe two layers. In addition, in the case of an iridium oxide layer asthe noble metal oxide, the oxygen depletion leaves that layer lesseffective as a stenosis or restenosis inhibitor.

SUMMARY OF THE INVENTION

[0018] Therefore, it is a principal goal of the present invention toprovide a body-implantable stent, and method of production thereof, inwhich a noble metal oxide surface coating on a stent having either anon-noble or a less-noble (than the surface coating) metal or alloysubstrate or core maintains desired characteristics and has an improvedbond to the underlying substrate.

[0019] According to the invention, in a process for producing a stenthaving multiple layers, a tubular substrate or core of the stent iscomposed of a less-noble or non-noble metal or alloy, such as niobium orplatinum-enriched medical grade stainless steel; an interface region isformed at a surface of the substrate or the confronting surface of thelayer of iridium oxide to be deposited thereon, the interface regionhaving characteristics preselected to prevent corrosion and to provide afirm bond between the surface of the substrate and the noble metal oxidelayer when deposited thereon, and the noble metal oxide layer is thendeposited on the surface of the substrate at the location where theinterface region is formed.

[0020] In an exemplary process for producing a biocompatible stent basedon that concept, a tubular substrate adapted for diametric expansion, alayer of a noble metal oxide is formed over at least the outer surfaceof greater diameter of the substrate, the substrate being composed of ametal or an alloy thereof that is non-noble or less-noble than the noblemetal, and at least partly establishing an interface region adapted toprevent corrosion and to provide a firm bond between the surface of thesubstrate and the noble metal oxide layer by forming the noble metaloxide layer with a progressively varying concentration of noblemetal-to-oxide with depth of said layer such that a surface of purenoble metal and negligible oxide of said layer is in closest proximityto the surface of the substrate.

[0021] In one embodiment or technique, the process may includeestablishing the interface region solely by forming the noble metaloxide layer with the surface of pure noble metal and negligible oxidethereof in direct contact with the metal or alloy of the surface of thesubstrate. In another, the process may include establishing theinterface region by first creating an oxide of the metal or alloythereof at the surface of the substrate to a thickness in a range fromapproximately 1 nm to approximately 500 nm, and then forming the noblemetal oxide layer with the surface of pure noble metal and negligibleoxide thereof overlying the oxide of the metal or alloy thereof at thesurface of the substrate. In still another, the process may includeestablishing the interface region by first creating either a nitricoxide or nitride of the metal or alloy thereof at the surface of thesubstrate to a thickness in a range from approximately 1 nm toapproximately 500 nm, and then forming the noble metal oxide layer withthe surface of pure noble metal and negligible oxide thereof overlyingthe nitric oxide or nitride of the metal or alloy thereof at the surfaceof the substrate. And in yet another embodiment or technique, theprocess may include establishing the interface region by first creatingan intermediate layer of either a nitric oxide or nitride of the noblemetal to a thickness in a range from approximately 1 nm to approximately500 nm overlying the surface of the substrate, and then forming thenoble metal oxide layer with the surface of pure noble metal andnegligible oxide thereof atop the intermediate layer.

[0022] Alternatively, the process may simply involve forming a noblemetal oxide layer overlying and in direct contact with an oxide of thesubstrate metal or alloy thereof, without any progressively varyingconcentration of noble metal-to-oxide in the noble metal oxide layer.For example, an iridium oxide layer is applied onto an underlyingsubstrate metal of non- or less-noble characteristic (for example, theaforementioned niobium or alloy thereof such as with an added trace ofzirconium, titanium or tantalum, or the aforementioned platinum-enrichedmedical grade stainless steel) that has been oxidized in at least asurface region intended to receive the iridium oxide layer, for stable,non-corrosive bonding of the two. The desired oxidation of the lessnoble metal (or alloy thereof) can be achieved by heating in anoxygen-rich environment, reverse electropolishing, or any otherconventional method. Forming the noble metal oxide layer in a desiredthickness on the exposed surface(s) of the stent may then beaccomplished by any conventional technique, such as by physical vapordeposition, or by chemical wet processing, so as to produce the desiredfirm bond between the oxide layer and the underlying less noble metal oralloy by virtue of the presence of the oxide region in the latter (e.g.,niobium oxide).

[0023] Oxidation of the less noble metal should be at least along theexposed surface region of the non- or less-noble metal substrate of thestent, if not throughout the thickness of the substrate. The existenceof niobium oxide in a primarily niobium substrate, for example, inhibitsleaching of oxygen from the overlying iridium oxide, and hence,maintains the desired characteristics of the iridium oxide layer for itsessential purpose of biocompatibility and avoidance of irritation andconsequent stenotic reaction of body tissue (such as the inner lining ofan artery wall) with which that layer is in contact when the stent isimplanted.

[0024] A coated stent according to the invention comprises a metallicsubstrate; and a coating of an oxide of noble metal overlying a surfaceregion of the substrate. The surface region is one of (i) asubstantially pure metal of lesser standing in the periodic table ofelements than the noble metal, (ii) an alloy, oxide, nitride, or nitricoxide of the lesser metal, and (iii) a nitride or nitric oxide of thenoble metal. The noble metal oxide coating progressively varies withthickness commencing at the surface region of the substrate, from aconcentration of the noble metal of substantially 100% purity withnegligible amount of oxide and other constituents, and ending at anopposite surface of the coating with a concentration of the noble metaloxide of stoichiometric equilibrium.

[0025] Another embodiment a multi-layer stent of the invention includesa tubular substrate composed primarily of a metal or alloy having theproperties discussed above; an interface region at a surface of thesubstrate having characteristics to inhibit corrosion and establish afirm bond between the surface of the substrate and a noble metal oxidelayer to be formed thereon; and the noble metal oxide layer coated onthe interface region of the surface of the substrate.

BRIEF DESCRIPTION OF THE DRAWING

[0026] The above and other aims, goals, objectives, features, aspectsand attendant advantages of the present invention will become apparentto those skilled in the art from a consideration of the followingdetailed description of a best mode presently contemplated of practicingthe invention by reference to certain preferred exemplary embodimentsand methods of manufacture thereof, taken in conjunction with theaccompanying drawing, in which:

[0027]FIG. 1 is a side perspective view of an exemplary embodiment of astent structure for use with the invention (in which the far side of thestructure is not shown through openings on the near side, for the sakeof simplicity and clarity);

[0028]FIG. 2 is an enlarged partial cross-sectional view through thelines 2-2 of the exemplary embodiment of FIG. 1, with greatlyexaggerated layer thicknesses;

[0029]FIGS. 3, 4 and 5 are still further enlarged partialcross-sectional views through the stent's substrate surface region,interface region and overlying noble metal oxide layer of threeexemplary embodiments, with greatly magnified layer thicknesses, and inwhich the noble metal oxide layer is depicted as a diagram of noblemetal concentration versus depth (or thickness) of the layer.

DETAILED DESCRIPTION OF BEST MODE OF PRACTICING THE INVENTION

[0030] It is to be understood that none of the drawing figures isintended to be a representation to scale of the respective depictedembodiment.

[0031]FIG. 1 is a perspective view of a stent 10 of hollow tubularself-supporting structure, with a substrate or core composed preferablyof niobium (Nb) with a trace of zirconium (Zr), titanium (Ti) ortantalum (Ta), for example, preferably zirconium, the trace amountpreferably being between approximately 1% and approximately 5%, and mostpreferably being about 2%, and remainder niobium. The added trace metalimproves physical characteristics including strength of the stent forits intended function. Typically, the niobium stent material includesnegligible amounts of tantalum (Ta, about 180 micrograms per gram(μg/g)), iron (Fe, <20 μg/g), silicon (Si, about<20 μg/g), tungsten (W,<20 μg/g), molybdenum (Mo, <20 μg/g), hafnium (Hf, <20 μg/g), carbon (C,about 7 μg/g), and nitrogen (N, about 53 μg/g), as well as amounts ofhydrogen (H) and oxygen (O) primarily introduced during the processing.Alternatively, a stent substrate suitable for the present invention maybe platinum-enriched (e.g., 20-30%) 316L medical grade stainless steel.

[0032] For a niobium stent substrate, the presently preferred process offabricating the stent is performed in the following sequence of steps:(1) tube processing from Nb-1%Zr ingots; (2) laser cutting of tube; (3)mechanical and chemical finishing; (4) electropolishing; (5) vacuumannealing; and (6) anodizing or sputtering with a surface coating ofiridium oxide.

[0033] In the laser cutting process, the tubular stent member isprovided with a multiplicity of through-holes or openings 12 throughsidewall 15, defined and bounded by a plurality of struts or links 13,which enables expansion of the stent diameter when the device is to bedeployed at a target site in a vessel, channel, duct or tract(collectively, vessel) of the human body. Precise cutting of openings 12to form a latticework sidewall is achieved using a conventional laserwith narrow beam following a programmable pattern.

[0034] The exemplary type of structure shown in FIG. 1 is described indetail in patent U.S. Pat. No. 6,398,805 of the same assignee. Thisconfiguration provides a relatively very low coefficient of friction ofthe outer surface 17, for easier advancement of stent 10 in the vesselto a target site for deployment. The latticework sidewall 15 has apattern of interconnected struts 13 optimized for orientationpredominantly parallel to the longitudinal axis 16 of the tube 11.Substantially none of the struts are oriented perpendicular (i.e.,transverse) to the axis 16. Thus, no strut interconnecting any otherstruts in the latticework is oriented to lie completely in a planetransverse to the longitudinal axis, without running from one end of thestent to the opposite end. The network or latticework of struts 13defines a series of longitudinally repeating circumferential rows 20 ofopenings 12, with each opening bounded by alternating links in waveletsof higher and lower crests (or shallower and deeper troughs, if FIG. 1is rotated 180°) in successive rows of each circumferential columndisplaced along the length of the cylindrical element.

[0035] Each pair of struts such as 21, 22 bounding an opening 12 in anygiven row 25 have the shape of circumferentially displaced wavelets withadjacent circumferentially aligned higher and lower crests 26, 27,respectively, in which the wavelets intersect (30) one another at one orboth sides of the crests (30, 31). The intersection 30 of struts (orwavelets) at one side of the adjacent circumferentially aligned crests26, 27 of row 25 is tangential to a crest 33 of the immediately adjacentrow 35, and the intersection 31 of struts (or wavelets) at the otherside of those crests is tangential to a crest 37 of the immediatelyadjacent row 38. Interconnecting points such as 40 between the strutsmay be notched to enhance symmetrical radial expansion of the stentduring deployment thereof.

[0036] When the stent 10 is crimped onto a small diameter (low profile)delivery balloon (not shown), the adjacent circumferentially alignedcrests of each row move closer together, and these portions tend towardfitting into each other, as the pattern formed by the latticework ofstruts allows substantial nesting together of the crests and bows, whichassures a relatively small circumference of the stent in the crimpedcondition. Such a stent is highly flexible, and is capable of undergoingbending to a small radius corresponding to radii of particularlytortuous coronary arteries encountered in some individuals, withcircumferentially adjacent struts along the inner portion of the bendmoving closer together while those along the outer portion of the bendspread further apart, without permanent plastic deformation.

[0037] As the stent 10 is partially opened by inflation of the balloonduring deployment, the adjacent crests begin to separate and the angleof division between struts begins to open. When the stent is fullyexpanded to its deployed diameter, the latticework of struts takes on ashape in which adjacent crests undergo wide separation, and portions ofthe struts take on a transverse, almost fully lateral orientationrelative to the longitudinal axis of the stent. Such lateral orientationof a plurality of the struts enables each fully opened cell tocontribute to the firm mechanical support of a scaffold provided by thestent when in its fully deployed condition. This assures a rigidstructure which is highly resistant to recoil of the vessel wallfollowing stent deployment. The particular configuration of the stentstructure shown in FIG. 1, while highly desirable, is illustrative only.

[0038] The stent may be pre-opened after fabrication to relievestresses. Pre-opening produces a stent inner diameter that allows thestent to slide comfortably over the uninflated mounting balloon, forease of crimping the stent onto the balloon. Annealing may be performedafter pre-opening by heating the stent structure to an appropriatetemperature for a predetermined interval of time.

[0039] The presently preferred niobium/zirconium material of the stentis fabricated in any conventional manner for producing alloys, with thezirconium amounting from 1% to 5% by weight, preferably about 2%, andthe remainder niobium. For example, the manufacturing process may beperformed by sintering particles or microspheres of the constituentmetals under heat and pressure. Rather than zirconium, a trace amount(e.g., one to three percent) of titanium or tantalum may be alloyed withniobium for added strength and other desirable physical characteristics.Other suitable alternative additive materials include those described inpatents U.S. Pat. No. 5,472,794 and U.S. Pat. No. 5,679,815, forexample. The alloy is then formed into tubing and the through holes areprovided in its side wall as described above.

[0040] The stent structure can be produced with a wall thickness ofabout 85 μm, which offers sufficient mechanical strength to resist thenatural recoil of the blood vessel wall following deployment of thestent, as well as excellent visibility under fluoroscopy, but which doesnot obstruct the vessel lumen to any significant extent. This stent haslittle or no distortion in a process of magnetic resonance imaging(MRI), and is highly beneficial for noninvasive monitoring of cerebraland peripheral vessels also.

[0041] To enhance the biocompatibility and antiproliferativecharacteristics of the stent after implantation the surfaces may becoated with a 10 to 1000 nanometers (nm) thick layer of iridium oxide(sometimes referred to herein as IROX). This may be accomplished by anyconventional process, such as physical vapor deposition (PVD). PVDencompasses a broad class of vacuum coating processes in which materialis physically removed from a source by evaporation or sputtering orlaser-induced sputtering, transported through a vacuum or partial vacuumby the energy of the vapor particles themselves or enhanced in anelectric field, and condensed as a film on the surfaces of appropriatelyplaced parts or substrates. Chemical compounds are deposited by eitherusing a similar source material, or by introducing a reactive gas(nitrogen, oxygen, or simple hydrocarbons) containing the desiredreactants, which react with metal(s) from the PVD source. In general,all PVD processes can be separated into three distinct phases, namely,(a) emission from a vapor source (target); (b) vapor transport invacuum; and (c) condensation on substrates to be coated.

[0042] The easiest substrates to coat are those that are electricallyconductive and remain stable (minimum outgassing or decomposition ofbulk material) at elevated temperatures. With metal substrates, certainmaterials, surface conditions, and assembling techniques must be avoidedto achieve good adhesion and film properties. For example, certainmetallic alloys create problems during coating if the temperatureexceeds a predetermined temperature (e.g., 390° F., equivalent to 200°C.) because of their high vapor pressures. Porous metals are generallydifficult to coat because oils and contaminants remain entrapped in thepores. Burrs must be removed from the substrate before coating toprevent exposure of uncoated metal when the burrs are later removed.Although some materials and assembly methods are undesirable for PVDcoatings, many of the problems described above can be overcome bythorough cleaning and by appropriate adjustment of operating parameters.However, since stents are basically tubes with holes and slots, theirconfiguration makes vapor deposition on the inner surfaces difficult.

[0043] Process conditions for an exemplary embodiment or technique todeposit IROX on stents composed of Nb metal or Nb-based alloys, shown inFIG. 2, are as follows:

[0044] a. The sputter target is iridium.

[0045] b. The stent substrates are affixed on small hooks, and undergocontinuous movement similar to the satellite cog of an planetary gear.Because the iridium ion stream is one-dimensional, the planetarymovement assures an IROX layer of homogeneous thickness and quality fromthe deposition process.

[0046] c. The recipient is evacuated.

[0047] d. The substrate is plasma etched, with preparation and minimalabrasion of the natural oxide layer on Nb alloys typically being a fewnanometers thick.

[0048] e. O₂ is introduced as reactive gas by keeping the stoichiometricratio of the resulting IROX coating.

[0049] f. Deposition is commenced by accelerating Ar ions onto theiridium target, and vaporization of Ir starts.

[0050] g. Ir vapor moves toward the plural stent substrates and becomesionized.

[0051] h. Shortly before reaching the substrate surface Ir ions reactwith O₂ to form IrO₂ (hence, the name “reactive sputtering”).

[0052] i. The kinetic energy of the ion stream makes the IrO₂ depositiondense and adhere sufficiently to the substrate surface.

[0053] j. The process is completed when an IrO₂ layer 45 of desiredthickness in a range between about 10 to about 1000 nanometers isdeposited on the surface 46 of substrate 47.

[0054] The relative thicknesses of the layers are greatly exaggerated inFIG. 2, and the surfaces, particularly the exposed surface of IROX layer45, are shown as being smooth merely for the sake of simplicity.

[0055] Another process that may be used for forming an iridium oxidelayer is conventional chemical deposition. Niobium and its alloys reduceIrO₂ to Ir+metal-oxide because of their high affinity to oxygen. Thiseffect occurs even during the deposition of IrO₂ when the last coatingstep transforms the precipitation of Ir₂O₃ on the stent surface inIr+IrO₂ after a last baking step. In the reaction, then, only Ir isdeposited on the surface of the Nb substrate, rather than IrO₂, as theless-noble metal, Nb, becomes oxidized on its surface beneath the Ircoating.

[0056] To avoid reducing Ir₂O₃ to Ir+metal oxide, any of the followingprocedures may be employed: (1) the surface of the less-noble metal maybe protected with a zone where the affinity to oxygen is low; or (2) anadditional oxide layer may be produced by pre-anodizing or -passivatingthe Nb substrate; or (3) using organic iridium compounds instead of asonolysis method as described in either of publications DE 19916315A1(Germany) or WO99/52471 (WIPO); or (4) coating the non- or less-noblemetal with a noble metal as described in either of the latterpublications.

[0057] Galvanic corrosion may be encountered when the coating materialdiffers from the substrate material, and especially when noble and non-or less-noble metals are electrically connected by the relationship ofcoating overlying the substrate, and then used in electrolytes such asblood or water. If the coating becomes cracked because of mechanicalstress, the metallic ions can get in solution into the electrolyte andcause corrosion of the substrate with attendant weakening of the bondwith the coating.

[0058] In the case of a substrate metal such as Nb or an alloy thereofand the deposited oxide of the noble element iridium, IrO₂, a similarprocess may occur. In brief, the high affinity of non-noble orless-noble metals to oxygen may reduce IrO₂ to Ir and oxygen in theinterface area between the substrate and the coating thereon as thelatter is deposited. This could possibly result in decreased adhesionover time, and lead to flaking of the deposited IrO₂ layer.

[0059]FIGS. 3, 4 and 5 are additional enlarged partial cross-sectionalviews through the stent's substrate surface region, interface region andoverlying noble metal oxide layer of three exemplary embodiments, withgreatly magnified layer thicknesses, and in which the noble metal oxidelayer is depicted as a diagram of noble metal concentration versus depth(or thickness) of the layer. That is, the layer designated 45 is agraphical depiction of how the iridium (in this example) concentrationin the IROX layer varies progressively with the depth of the layer. Inthe chart or graph, the vertical (y) axis represents percentageconcentration of a constituent, and the horizontal (x) axis representsdepth (or thickness) of the structural component (in this case, the IROXlayer), i.e., reference number 51 indicates concentration of Ir alongthe coating or layer depth. It is not to be taken as indicating that thewidth of the IROX layer undergoes a change with depth or thickness;rather, the width remains constant.

[0060] In each of FIGS. 3, 4 and 5 (and FIG. 2 as well), the followingreference number indications apply: 45: IROX coating; 46: Ir layer:; 47:niobium (Nb) substrate (non-noble or less-noble metal or alloy); 49:oxide of substrate 47; 50: stoichiometric equilibrium of IrO₂; 51:concentration of Ir along coating depth; 52: concentration of O alongcoating depth; 53: layer of Nb nitric oxide or Ir nitric oxide or Nbnitride or Ir nitride. On the graphical portion of the chart shown inthe Figures, 51 shows that the concentration of Ir diminishesprogressively with distance from the surface of the non-noble orless-noble substrate 47, which is in closest proximity to the maximumconcentration of the Ir. It should be emphasized that reference number50 is as stated above; it is not associated with a percentageconcentration of any constituent of the layer on the y-axis.

[0061] According to the invention, the problems resulting from anattempted adhesion or bonding of two metals of different nobleness canbe avoided by special preparation of the substrate, by either of twodistinct and different means or techniques, as follows:

[0062] 1. The non- or less-noble substrate (niobium, alloyed with thetrace of zirconium or other metal as described above) is anodized beforethe noble metal oxide (e.g., IrO₂) layer is deposited. This can be agalvanic process where the substrate surface becomes oxidized andpassivated, or the passivation is achieved by other means such assputtering. An oxide surface region 49 of selected thickness in a rangefrom about 1 to about 500 nanometers (nm) is formed on the substrate 47by the anodizing step, and this surface becomes the interface for thesubsequently deposited IROX layer coating, to protect the substrate fromdirect contact with IrO₂ (FIG. 4).

[0063] 2. Alternatively, during the PVD process, a second preparationstep (after plasma etching) is introduced, comprising a selected one ofthe following three alternatives:

[0064] a. The partial pressure of the reactive gas oxygen iscontinuously increased from zero to the pressure keeping thestoichiometric ratio of IrO₂. The resulting IROX layer 45 progressivelyvaries from virtually pure (substantially 100%) Ir on the substratesurface 46 to a greatest concentration of iridium oxide at the outersurface 50 of the coating. An interfacial reaction between oxides of thenon- or less-noble substrate metal (e.g., Nb₂O₅—niobium pentoxide) andof the noble iridium is not possible. This protects the interface areafrom corrosion as well (FIG. 3).

[0065] b. An interlayer of the substrate oxide (e.g., Nb₂O₅) is producedby using a double-target equipped PVD apparatus. One target is composedof the substrate material, and the other is composed of Ir. For coatinga substrate oxide the process is similar to that run for IROXdeposition, but using the target of substrate material. After achievingan oxide of selected thickness in a range from about 1 to about 500nanometers the targets are flipped, continuing with the IROX coating.

[0066] c. Introducing nitrogen as a second reactive gas produces aninterlayer of a very resistant composition of metal nitric oxides or analloy of metal nitrite and metal oxide 53 (FIG. 5). This is possible assubstrate metal nitric oxide or nitrite and oxide using double-targetPVD (e.g., Nb nitric oxide) or as Ir nitric oxide or Ir nitrite andoxide which is converted to IrO₂ by following the procedure described in2.a., immediately above The affinity of niobium or Nb-based alloys tonitrogen is low, resulting in a more stable coating stack.

[0067] Although a best mode of practicing the invention has beendisclosed by reference to a preferred method and embodiment, it will beapparent to those skilled in the art from a consideration of theforegoing description that variations and modifications may be madewithout departing from the spirit and scope of the invention.Accordingly, it is intended that the invention be limited only by theappended claims and the rules and principles of applicable law.

What is claimed is:
 1. In a process for producing a biocompatible stent,providing a tubular substrate adapted for diametric expansion, forming alayer of a noble metal oxide over at least the outer surface of greaterdiameter of said substrate, said substrate being composed of a metal oran alloy thereof that is non-noble or less-noble than said noble metal,and at least partly establishing an interface region adapted to preventcorrosion and to provide a firm bond between said surface of thesubstrate and said noble metal oxide layer by forming the noble metaloxide layer with a progressively varying concentration of noblemetal-to-oxide with depth of said layer such that a surface of purenoble metal and negligible oxide of said layer is in closest proximityto said surface of the substrate.
 2. The process of claim 1, includingestablishing said interface region solely by forming said noble metaloxide layer with said surface of pure noble metal and negligible oxidethereof in direct contact with the metal or alloy of said surface of thesubstrate.
 3. The process of claim 1, including establishing saidinterface region by first creating an oxide of the metal or alloythereof at said surface of the substrate to a thickness in a range fromapproximately 1 nm to approximately 500 nm, and then forming said noblemetal oxide layer with said surface of pure noble metal and negligibleoxide thereof overlying said oxide of the metal or alloy thereof at saidsurface of the substrate.
 4. The process of claim 3, including creatingsaid oxide of the metal or alloy thereof at said surface of thesubstrate by oxidizing a surface region to a depth in a range fromapproximately 1 nm to approximately 500 nm from said surface of thesubstrate, and then forming said noble metal oxide layer with saidsurface of pure noble metal and negligible oxide thereof in directcontact with said surface of the substrate.
 5. The process of claim 1,including establishing said interface region by first creating either anitric oxide or nitride of the metal or alloy thereof at said surface ofthe substrate to a thickness in a range from approximately 1 nm toapproximately 500 nm, and then forming said noble metal oxide layer withsaid surface of pure noble metal and negligible oxide thereof overlyingsaid nitric oxide or nitride of the metal or alloy thereof at saidsurface of the substrate.
 6. The process of claim 1, includingestablishing said interface region by first creating an intermediatelayer of either a nitric oxide or nitride of said noble metal to athickness in a range from approximately 1 nm to approximately 500 nmoverlying said surface of the substrate, and then forming said noblemetal oxide layer with said surface of pure noble metal and negligibleoxide thereof atop said intermediate layer.
 7. The process of claim 1,including forming said noble metal oxide layer to a thickness in a rangefrom approximately 10 nm to approximately 1000 nm.
 8. The process ofclaim 1, wherein said noble metal is iridium.
 9. The process of claim 8,wherein said non-noble or less-noble metal is niobium.
 10. The processof claim 8, wherein said stent substrate is composed of a metal or alloyless noble than niobium.
 11. A process for producing a coated stent,comprising the steps of forming a metal oxide region at a surface of thestent metal substrate; and providing a noble metal oxide layer atop saidmetal oxide substrate surface region, said layer progressively varyingfrom a surface concentration of substantially 100% pure noble metaldirectly contacting said metal oxide substrate surface region to anopposite surface concentration of least noble metal; the surface regionmetal being non-noble or less-noble than said noble metal.
 12. Theprocess of claim 11, wherein said metal oxide surface region extends toa depth in a range from approximately 1 to approximately 500 nm into thesubstrate from said surface of the substrate.
 13. The process of claim12, including forming said noble metal oxide layer to a thickness in arange from approximately 10 nm to approximately 1000 nm on said surfaceof the substrate.
 14. The process of claim 11, wherein said noble metalis iridium.
 15. The process of claim 11, wherein said substrate metal iseither niobium or an alloy of niobium.
 16. A coated stent, comprising ametallic substrate; and a coating of an oxide of noble metal overlying asurface region of the substrate; said surface region being one of (i) asubstantially pure metal of lesser standing in the periodic table ofelements than said noble metal, (ii) an alloy, oxide, nitride, or nitricoxide of said lesser metal, and (iii) a nitride or nitric oxide of saidnoble metal; said noble metal oxide coating progressively varying withthickness commencing at said surface region of the substrate, from aconcentration of said noble metal of substantially 100% purity withnegligible amount of oxide and other constituents, and ending at anopposite surface of said coating with a concentration of the noble metaloxide of stoichiometric equilibrium.
 17. The coated stent of claim 16,wherein said noble metal is iridium, and said lesser metal is selectedfrom a group consisting of (i) niobium and (ii) niobium alloyed with atrace of zirconium, titanium or tantalum.
 18. The coated stent of claim16, wherein said surface region has a thickness in the range fromapproximately 1 nm to approximately 500 nm.
 19. The coated stent ofclaim 16, wherein said noble metal oxide coating has a thickness in arange from approximately 10 nm to approximately 1000 nm.
 20. Amulti-layer stent, comprising: an open-ended tubular metallic sidewalladapted to be expanded from a relatively small diameter adapted foradvancement of the stent through a patient's body vessel to a deploymenttarget site, to a relatively larger diameter for engaging the wall ofsaid vessel to maintain an open lumen at said site; an iridium oxideouter layer of said stent about the larger diameter surface of saidsidewall; and an interface bonding region along said larger diametersurface of said sidewall and said surface of the iridium oxide layerclosest thereto, consisting of one of (i) an alloy, oxide, nitride, ornitric oxide of metal of said sidewall, and (ii) a nitride or nitricoxide of iridium; said sidewall metal being either non-noble or lessnoble than iridium.
 21. The multi-layer stent of claim 20, wherein saidsidewall metal is one of (i) niobium, (ii) niobium alloyed with a traceof zirconium, titanium or tantalum, or (iii) a metal either non-noble orless noble than niobium.
 22. The multi-layer stent of claim 20, whereinsaid interface bonding region has a thickness in a range fromapproximately 1 nm to approximately 500 nm.
 23. The multi-layer stent ofclaim 20, wherein said iridium oxide layer has a thickness in a rangefrom approximately 10 nm to approximately 1000 nm.
 24. A process forproducing a stent coated with iridium oxide where the stent metal isless noble than iridium, comprising the steps of coating the iridiumoxide on an outer surface of the stent by forming an interface toenhance firm bonding without corrosion between the stent and the iridiumoxide coating while preventing direct contact between bare metal of thestent and any iridium oxide compound of the coating.